# CRH

## Overview
The CRH gene encodes the corticotropin-releasing hormone (CRH), a pivotal peptide hormone involved in the stress response and various physiological processes. CRH is primarily synthesized in the hypothalamus and acts by stimulating the secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland, which in turn influences cortisol release from the adrenal glands. This hormone cascade is essential for the body's ability to respond to stress. The protein itself is not categorized as a kinase, receptor, or transmembrane protein but functions through interaction with its receptors, CRHR1 and CRHR2, which are G-protein-coupled receptors (GPCRs). These interactions facilitate a wide range of biological functions, including stress response, immune modulation, and metabolic regulation (VAMVAKOPOULOS1994Hormonal; Bonfiglio2011The).

## Structure
The molecular structure of corticotropin-releasing hormone (CRH) includes three main functional domains that are crucial for its interaction with CRH receptors. The first domain, comprising residues 1-16, is essential for both binding and receptor activation. The second domain, residues 17-31, serves as a linker and contains the CRH-BP binding site with the ARAE motif (Ala-Arg-Ala-Glu), providing spatial and conformational support for the binding regions. The third domain, residues 32-41, plays a significant role in receptor binding (Hillhouse2006The).

Specific amino acid residues within these domains contribute to the selectivity for CRH receptor subtypes. For instance, a proline at position 11, found in CRH-R2 selective peptides, introduces a kink or turn motif that decreases α-helicity and impairs binding to CRH-R1. Additionally, CRH-R2 selective peptides contain alanine residues at positions 35 and 39, whereas CRH-R nonselective peptides have an arginine at position 35 and an acidic amino acid at position 39 (Hillhouse2006The).

Post-translational modifications such as glycosylation are crucial for cell surface expression and occur predominantly in the N-terminal extracellular domain of CRH receptors, which contains multiple N-glycosylation sites (Dautzenberg2001Molecular). These modifications are essential for the proper function and interaction of the hormone with its receptors.

## Function
The CRH gene encodes corticotropin-releasing hormone (CRH), a peptide that plays a central role in the stress response by regulating the hypothalamic-pituitary-adrenal (HPA) axis. CRH is synthesized in the hypothalamus and stimulates the secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland, which in turn promotes cortisol release from the adrenal glands. This hormone cascade is crucial for helping the body manage and respond to stress (VAMVAKOPOULOS1994Hormonal).

Beyond its role in stress response, CRH influences various physiological and behavioral responses through its receptors, CRHR1 and CRHR2, which are expressed in multiple central and peripheral sites including the nervous system, immune cells, and other organs. These receptors are involved in processes such as blood pressure regulation, arousal, and modulation of immune responses (VAMVAKOPOULOS1994Hormonal).

In the skin, CRH functions as a growth factor and cytokine, influencing cellular processes such as differentiation and immune activity. It interacts with its receptor, CRH-R1, to activate different signaling pathways depending on the cell type, which includes the production of cAMP and IP3, crucial for cell differentiation and proliferation (Slominski2005CRH).

CRH also plays a role in modulating the immune response, as evidenced by its ability to stimulate the expression of cell adhesion molecules and HLA-DR antigen in human neonatal keratinocytes in response to interferon-gamma (SLOMINSKI2001Cutaneous). This multifunctional peptide thus has significant implications not only in stress management but also in various cellular functions and immune regulation across different tissues.

## Clinical Significance
Mutations and alterations in the expression of the CRH gene have been linked to a variety of psychiatric and physiological disorders. Elevated levels of CRH have been observed in the cerebrospinal fluid of patients with post-traumatic stress disorder (PTSD) and depression, suggesting a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis that is characterized by increased secretion of adrenocorticotropic hormone (ACTH) and cortisol in response to CRH hyperactivity (Laryea2012Behavioral). This hyperactivity is also the most commonly observed neuroendocrine change in major depressive disorder (MDD), indicating that normalization of the HPA axis might be necessary for effective treatment in some patients (Laryea2012Behavioral).

Furthermore, genetic polymorphisms in the CRH gene have been associated with behavioral inhibition, a predictor of anxiety disorders. Specific alleles at the CRH locus have been shown to influence the likelihood of exhibiting behavioral inhibition, potentially affecting the risk of developing anxiety disorders later in life (Laryea2012Behavioral).

In addition to psychiatric conditions, CRH gene mutations have been implicated in physiological disorders such as central serous chorioretinopathy (CSC). A specific heterozygous insertion variant in the CRH gene was found to decrease CRH gene expression and was strongly associated with CSC in Chinese cohorts, highlighting the role of the HPA stress response system in this vision-affecting condition (Jin2022An).

These findings underscore the critical role of CRH in both mental health and physiological processes, suggesting that targeted therapies that address CRH dysregulation may be effective in treating these diverse conditions.

## Interactions
CRH (corticotropin-releasing hormone) interacts with several proteins that modulate its function and signaling pathways. One of the primary interactions is with its receptors, CRHR1 and CRHR2, which are G-protein-coupled receptors (GPCRs). CRH binds with high affinity to CRHR1 and less effectively to CRHR2, influencing various physiological processes including stress response (Bonfiglio2011The). Additionally, CRH interacts with the CRH-binding protein (CRH-BP), which binds CRH with high affinity, potentially modulating its biological activity by inhibiting its action, particularly in regulating pituitary ACTH secretion (Ketchesin2017Corticotropin-releasing; Turnbull1997Corticotropin-Releasing).

CRH also activates several signaling pathways through its interaction with CRHR1. It can trigger the adenylate cyclase/protein kinase A (PKA) pathway, leading to the activation of downstream targets such as the MAPK pathway elements ERK1/2 (Bonfiglio2011The). Moreover, CRH is involved in the activation of ERK1/2 through cAMP/PKA pathways in corticotrophs and can influence the activation of ERK1/2 and p38 in HEK293 cells via CRHR1 (Bonfiglio2011The).

These interactions highlight the complex regulatory mechanisms of CRH in stress response and other physiological functions, mediated through its binding to specific receptors and proteins.


## References


[1. (Laryea2012Behavioral) Gloria Laryea, Melinda G. Arnett, and Louis J. Muglia. Behavioral studies and genetic alterations in corticotropin-releasing hormone (crh) neurocircuitry: insights into human psychiatric disorders. Behavioral Sciences, 2(2):135–171, June 2012. URL: http://dx.doi.org/10.3390/bs2020135, doi:10.3390/bs2020135. (68 citations) 10.3390/bs2020135](https://doi.org/10.3390/bs2020135)

[2. (Jin2022An) En-Zhong Jin, Tian-Qi Li, Chi Ren, Li Zhu, Wei Du, Jin-Feng Qu, Yu-Ou Yao, Xiao-Xin Li, Peng Zhou, Lv-Zhen Huang, and Ming-Wei Zhao. An insertion variant in crh confers an increased risk of central serous chorioretinopathy. Investigative Opthalmology & Visual Science, 63(9):9, August 2022. URL: http://dx.doi.org/10.1167/iovs.63.9.9, doi:10.1167/iovs.63.9.9. (4 citations) 10.1167/iovs.63.9.9](https://doi.org/10.1167/iovs.63.9.9)

[3. (Hillhouse2006The) Edward W. Hillhouse and Dimitris K. Grammatopoulos. The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocrine Reviews, 27(3):260–286, May 2006. URL: http://dx.doi.org/10.1210/er.2005-0034, doi:10.1210/er.2005-0034. (468 citations) 10.1210/er.2005-0034](https://doi.org/10.1210/er.2005-0034)

[4. (Bonfiglio2011The) Juan José Bonfiglio, Carolina Inda, Damián Refojo, Florian Holsboer, Eduardo Arzt, and Susana Silberstein. The corticotropin-releasing hormone network and the hypothalamic-pituitary-adrenal axis: molecular and cellular mechanisms involved. Neuroendocrinology, 94(1):12–20, 2011. URL: http://dx.doi.org/10.1159/000328226, doi:10.1159/000328226. (202 citations) 10.1159/000328226](https://doi.org/10.1159/000328226)

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[6. (SLOMINSKI2001Cutaneous) ANDRZEJ SLOMINSKI, JACOBO WORTSMAN, ALEXANDER PISARCHIK, BLAZEJ ZBYTEK, ELIZABETH A. LINTON, JOSEPH E. MAZURKIEWICZ, and EDWARD T. WEI. Cutaneous expression of corticotropin‐releasing hormone (crh), urocortin, and crh receptors. The FASEB Journal, 15(10):1678–1693, August 2001. URL: http://dx.doi.org/10.1096/fj.00-0850rev, doi:10.1096/fj.00-0850rev. (337 citations) 10.1096/fj.00-0850rev](https://doi.org/10.1096/fj.00-0850rev)

[7. (Slominski2005CRH) A. Slominski, B. Zbytek, A. Pisarchik, R.M. Slominski, M.A. Zmijewski, and J. Wortsman. Crh functions as a growth factor/cytokine in the skin. Journal of Cellular Physiology, 206(3):780–791, October 2005. URL: http://dx.doi.org/10.1002/jcp.20530, doi:10.1002/jcp.20530. (134 citations) 10.1002/jcp.20530](https://doi.org/10.1002/jcp.20530)

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